Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis

Abstract

There are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma samples were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modeling was conducted using Pmetrics. Nine patients were recruited, and a two-compartment model adequately described the data. The piperacillin clearance (CL), volume of distribution of the central compartment (V_c), and distribution rate constants from the central to the peripheral compartment and from the peripheral to the central compartment were 5.6 ± 3.2 liters/h, 14.5 ± 6.6 liters, 1.5 ± 0.4 h^-1, and 1.8 ± 0.9 h^-1, respectively, where CL and V_c were found to be described by creatinine clearance (CL_CR) and total body weight, respectively. In this patient population, piperacillin demonstrated high interindividual pharmacokinetic variability. CL_CR was found to be the most important determinant of piperacillin pharmacokinetics.

FIG 1

Diagnostics of final pharmacokinetic model. (A) Plot of population predicted concentrations versus observed concentrations. (B) Plot of individual predicted concentrations versus observed concentrations (where the data presented on both the x and y axes are concentrations in milligrams per liter). (C) Visual predictive check plot (where output on the y axis is concentration in milligrams per liter).